Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons.

Hypothalamic neurons show sex differences in neuritogenesis, female neurons have longer axons and higher levels of the neuritogenic factor neurogenin 3 (Ngn3) than male neurons in vitro. Moreover, the effect of 17-ß-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the "four core genotypes" mouse model, in which the factors of "gonadal sex" and "sex chromosome complement" are dissociated. We showed that sex differences in neurite outgrowth are determined by sex chromosome complement (XX > XY). Moreover, E2 increased the mRNA expression of Ngn3 and axonal length only in XY neurons. ERα/ß expressions are regulated by sex chromosome complement; however, E2-effect on Ngn3 expression in XY neurons was only fully reproduced by PPT, a specific ligand of ERα, and prevented by MPP, a specific antagonist of ERα. Together our data indicate that sex chromosomes regulate early development of hypothalamic neurons by orchestrating not only sex differences in neuritogenesis, but also regulating the effect of E2 on Ngn3 expression through activation of ERα in hypothalamic neurons.

Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons.

Female mouse hippocampal and hypothalamic neurons growing in vitro show a faster development of neurites than male mouse neurons. This sex difference in neuritogenesis is determined by higher expression levels of the neuritogenic factor neurogenin 3 in female neurons. Experiments with the four core genotype mouse model, in which XX and XY animals with male gonads and XX and XY animals with female gonads are generated, indicate that higher levels of neurogenin 3 in developing neurons are determined by the presence of the XX chromosome complement. Female XX neurons express higher levels of estrogen receptors than male XY neurons. In female XX neurons, neuronal derived estradiol increases neurogenin 3 expression and neuritogenesis. In contrast, neuronal-derived estradiol is not able to upregulate neurogenin 3 in male XY neurons, resulting in decreased neuritogenesis compared to female neurons. However, exogenous testosterone increases neurogenin 3 expression and neuritogenesis in male XY neurons. These findings suggest that sex differences in neuronal development are determined by the interaction of sex chromosomes, neuronal derived estradiol and gonadal hormones.

[Bardet-Biedl syndrome: cilia and obesity - from genes to integrative approaches]. / Syndrome de Bardet-Biedl: cils et obésité - de la génétique aux approches intégratives.

The primary cilium is a specialized organelle, present at the surface of most eukaryotic cells, whose main function is to detect, integrate and transmit intra- and extra-cellular signals. Its dysfunction usually results in a group of severe clinical manifestations nowadays termed ciliopathies. The latter can be of syndromic nature with multi-organ dysfunctions and can also be associated with a morbid obese phenotype, like it is the case in the iconic ciliopathy, the Bardet Biedl syndrome (BBS). This review will discuss the contribution of the unique context offered by the emblematic BBS for understanding the mechanisms leading to obesity via the involvement of the primary cilium together with identification of novel molecular players and signaling pathways it has helped to highlight. In the current context of translational medicine and system biology, this article will also discuss the potential benefits and challenges posed by these techniques via multi-level approaches to better dissect the underlying mechanisms leading to the complex condition of obesity.

Molecular mechanisms involved in the regulation of neuritogenesis by estradiol: Recent advances.

This review analyzes the signaling mechanisms activated by estradiol to regulate neuritogenesis in several neuronal populations. Estradiol regulates axogenesis by the activation of the mitogen activated protein kinase (MAPK) cascade through estrogen receptor α located in the plasma membrane. In addition, estradiol regulates MAPK signaling via the activation of protein kinase C and by increasing the expression of brain derived neurotrophic factor and tyrosine kinase receptor B. Estradiol also interacts with the signaling of insulin-like growth factor-I receptor through estrogen receptor α, modulating the phosphoinositide-3 kinase signaling pathway, which contributes to the stabilization of microtubules. Finally, estradiol modulates dendritogenesis by the inhibition of Notch signaling, by a mechanism that, at least in hippocampal neurons, is mediated by G-protein coupled receptor 30. This article is part of a Special Issue entitled 'Neurosteroids'.